Activation of the unfolded protein response enhances motor recovery after spinal cord injury.
Activation of the unfolded protein response enhances motor recovery after spinal cord injury.
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DOI：
10.1038/cddis.2012.8
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发表时间：
2012-02-16
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
脊髓损伤（Spinal cord injury，SCI）是导致瘫痪的主要原因，涉及多种细胞和组织反应，包括脱髓鞘、炎症、细胞死亡和轴突变性。最近的证据表明，在不同的SCI模型中观察到内质网（ER）的稳态扰动;然而，这种途径对这种病理学的功能贡献尚不清楚。在这里，我们证明了SCI触发快速ER应激反应（1-3小时），涉及未折叠蛋白反应（UPR）的关键组分的上调，这是一个通过脊髓传播的过程。X-box结合蛋白1（XBP 1）或转录激活因子4（ATF 4）的表达，两个主要的UPR转录因子的消融，导致减少实验性SCI后的运动恢复。UPR失活的影响与受损轴突数量的显著增加和损伤区周围少突胶质细胞数量的减少有关。此外，在SCI后ATF 4缺陷小鼠中观察到改变的小胶质细胞活化和促炎细胞因子表达。使用腺相关病毒将活性XBP 1局部表达到脊髓中增强了SCI后的运动恢复，并且与少突胶质细胞数量的增加有关。总之，我们的研究结果证明了UPR在SCI中的功能性作用，为治疗这种无效状况提供了新的治疗靶点。
Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1–3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition.
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影响因子：
6.2
作者：
Ohri, Sujata Saraswat;Maddie, Melissa A.;Whittemore, Scott R.
通讯作者：
Whittemore, Scott R.
影响因子：
5.3
作者：
Galehdar, Zohreh;Swan, Patrick;Cregan, Sean P.
通讯作者：
Cregan, Sean P.
影响因子：
3.3
作者：
Penas, C.;Verdu, E.;Casas, C.
通讯作者：
Casas, C.
DOI：
10.1523/jneurosci.4065-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
通讯作者：
Court FA
ATF4是在体外和体内神经元中转录因子的氧化应激诱导的。
影响因子：
15.3
作者：
Lange, Philipp S.;Chavez, Juan C.;Pinto, John T.;Coppola, Giovanni;Sun, Chiao-Wang;Townes, Tim M.;Geschwind, Daniel H.;Ratan, Rajiv R.
通讯作者：
Ratan, Rajiv R.